Skeletal muscle atrophy is a debilitating disorder that is characterized by profound muscle wasting during adulthood. Atrophy results from decreased muscle use and is a pathologic feature of several myopathic diseases including amyotrophic lateral sclerosis, cancer and AIDS. Although it is clear that skeletal muscle wasting is caused by defects in postnatal muscle development and maintenance, the precise molecular mechanisms controlling myogenesis after birth are poorly understood and effective therapies to treat muscle atrophy are lacking. MicroRNAs (miRs) are attractive candidates to investigate during muscle development and disease because they are powerful regulators of post-transcriptional gene regulation and are dysregulated in multiple muscle disorders. The overall goal of this project is to elucidate the molecular mechanisms whereby miRs modulate skeletal muscle development and to determine if miR-based therapeutics are useful for treating muscle wasting. The observation that miR-29 is postnatally regulated and becomes most abundant as skeletal muscles reach their maximum mass suggests that miR-29 may function to maintain skeletal muscle homeostasis during adulthood. This hypothesis will be tested by characterizing postnatal muscle development in miR-29 skeletal muscle-specific gain-of- and loss-of-function transgenic mice. miR-29 overexpressor and knockout mice will also be used to identify the mRNAs and biochemical pathways that miR-29 regulates during postnatal skeletal muscle development. This aim of the project will result in fundamental knowledge regarding the nature of microRNA-mediated post-transcriptional control of postnatal skeletal muscle development. This second portion of this project will focus on investigating if miR-29 modulation has therapeutic potential for treating skeletal muscle wasting. Interestingly, miR-29 levels are elevated at very early stages of denervation-induced skeletal muscle atrophy. This suggests that miR-29 may promote muscle wasting and that miR-29 inhibition may serve as a protective mechanism to prevent or treat muscle atrophy. This possibility will be investigated by determining if miR-29 muscle-specific knockout mice are resistant to injury-induced skeletal muscle atrophy. The onset and progression of muscle atrophy will be monitored in de-nervated wild type and miR-29 mutant mice subjected to sciatic nerve dissection. This portion of the project aims to apply the basic knowledge learned from Aim 1 to extend healthy life by reducing the burdens of adult-onset muscle wasting. PUBLIC HEALTH RELEVANCE: Project Narrative The goal of this project is to explore the mechanisms of action of a microRNA during skeletal muscle development and to use our understanding of microRNA biology to uncover novel pathogenic mechanisms and therapies to treat skeletal muscle wasting.